The central theme of our research can be summarized in the question Why is the low infectivity of human T-cell leukemia virus type 1 (HTLV-1) advantageous for the virus? The answer to this question is important for developing strategies to deal with HTLV-1-associated pathologies, which include adult T-cell leukemia and degenerative neurological disorders. We believe that these strategies will be revealed in studies that examine the HTLV-1 infectious cycle with respect to 1) events surrounding the assembly and transmission of virus particles; 2) reverse transcription; and 3) virus interactions with cellular restriction factors. Our understanding of the HTLV-1 infectious cycle lags behind that of HIV-1 because HTLV-1 does not spread in established T-cell lines like HIV-1. More than a decade ago, we constructed one of the first infectious molecular clones of HTLV-1, and later we developed vectors and cell culture methods that made it possible to analyze HTLV-1 replication in vitro. These tools are now an essential complement to biochemical and molecular methods that are used to study HTLV-1 infection and replication. We have begun to construct analogous vectors for bovine leukemia virus (BLV) and HTLV-2, -3, and -4 to take advantage of the biological and genetic diversity among the deltaretroviruses for comparative analyses. The experiments that are planned here to examine molecular mechanisms of HTLV-1 infection and replication address several questions of current general interest in our field. These include mechanisms of Gag targeting to specific membrane domains via interactions between the matrix domain of Gag and lipid and/or protein components of the membrane; pathways of assembly and release for viruses that use a PPXY late domain; mechanisms that coordinate Gag and Env assembly; and mechanisms of retroviral inhibition by, and resistance to, cellular restriction factors belonging to the APOBEC family of cytidine deaminases. [Corresponds to Derse Project 1 in the April 2007 site visit report of the HIV Drug Resistance Program]